Blood-brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls.

Increased blood-brain barrier (BBB) permeability for ammonia is considered to be an integral part of the pathophysiology of hepatic encephalopathy (HE) in patients with liver cirrhosis. Increased glutamate-/glutamine-signal intensity in magnetic resonance spectroscopic studies of the brain in cirrhotic patients was explained as a consequence of increased cerebral ammonia uptake. As similar spectroscopic alterations are present in patients with liver fibrosis, we hypothesized that BBB permeability for ammonia is already increased in liver fibrosis, and thereby contributing to the development of HE. To test this hypothesis, cerebral perfusion and ammonia metabolism were examined through positron emission tomography with (15)O-water, respectively, (13)N-ammonia in patients with Ishak grades 2 and 4 fibrosis, cirrhosis, and healthy controls. There were neither global nor regional differences of cerebral blood flow, the rate constant of unidirectional transport of ammonia from blood into brain tissue, the permeability surface area product of the BBB for ammonia, the net metabolic clearance rate constant of ammonia from blood into glutamine in brain, or the metabolic rate of ammonia. The hypothesis that increased permeability of the BBB for ammonia in patients with liver fibrosis contributes to the later development of HE could not be supported by this study.

Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is considered to be mainly caused by increased ammonia metabolism of the brain. If this hypothesis is true, cerebral glucose utilisation, which is considered to represent brain function, should be closely related to cerebral ammonia metabolism. The aim of the present study was to analyse whether cerebral ammonia and glucose metabolism in cirrhotic patients with early grades of hepatic encephalopathy are as closely related as could be expected from current hypotheses on hepatic encephalopathy. METHODS: (13)N-ammonia and (18)F-fluorodesoxyglucose positron emission tomography, magnetic resonance imaging and magnetic resonance spectroscopy (MRS) were performed in 21 cirrhotic patients with grade 0-1 hepatic encephalopathy. Quantitative values of cerebral ammonia uptake and retention rate and glucose utilisation were derived for several regions of interest and were correlated with the MRS data of the basal ganglia, white matter and frontal cortex. RESULTS: A significant correlation between plasma ammonia levels and cerebral ammonia metabolism, respectively, and MRS alterations could be shown only for white matter. In contrast, MRS alterations in all three regions studied were significantly correlated with the glucose utilisation of several brain regions. Cerebral ammonia and glucose metabolism were not correlated. CONCLUSION: Increase of cerebral ammonia metabolism is an important but not exclusive causal factor for the development of hepatic encephalopathy.

Bradykinesia in cirrhotic patients with early hepatic encephalopathy is related to a decreased glucose uptake of frontomesial cortical areas relevant for movement initiation.

BACKGROUND/AIMS: Bradykinesia is one of the first symptoms of hepatic encephalopathy (HE). Recently it has been suggested that bradykinesia in HE is due to disturbances in movement initiation. Areas involved in self-initiated movement are the motor- and premotor cortex, the supplementary motor cortex, the motor areas of the cingulate gyrus, and part of the frontomesial- and parietal cortex. The present study aimed to test the hypothesis that bradykinesia in HE is due to a functional disturbance of these areas. METHODS: Fourteen cirrhotics with grade 0-I HE were examined. Patients with alcoholic cirrhosis or concomitant cerebral disorder were excluded. Patients underwent a 3-dimensional computer-assisted movement analysis for forearm pronation and supination, hand tapping and finger tapping and a (18)F-fluorodesoxy-glucose-PET-examination during rest, analysed with statistical parametric mapping (SPM99). RESULTS: The frequency of finger- and hand tapping was significantly correlated to the glucose metabolism of the motor area of the cingulate gyrus and frontomedial, frontodorsal and parietal cortical areas known to be activated with self-initiated movements. A decrease of movement frequency was associated with a reduction of glucose metabolism within these areas. CONCLUSIONS: These data support the hypothesis that bradykinesia in cirrhotics with HE is caused by an alteration of movement initiation.

Attention, memory, and cognitive function in hepatic encephalopathy.

Deficits in attention and arousal play a major role in the clinical presentation of hepatic encephalopathy. Attention deficits are also the main components of minimal hepatic encephalopathy. The present paper summarizes some findings about attentional and memory dysfunction in hepatic encephalopathy, with reference to basic knowledge about normal attention and memory function and their cerebral representation.

Neurological and neuropsychiatric syndromes associated with liver disease.

The clinical presentation of acute liver failure and hepatic encephalopathy (HE) in patients with cirrhosis differs significantly. The most serious neurological complication of acute liver failure is the development of devastating brain oedema. Therefore, intracranial pressure monitoring is urgently needed in these patients. Brain oedema is amplified by hypoglycemia, hypoxia and seizures, which are also frequent complications of acute liver failure. Therefore, these parameters must also be monitored. In contrast to acute liver failure in which cerebral dysfunction progresses rapidly, cognitive decline may be clinically undetectable for a long time in cirrhotic patients, until clinically overt symptoms such as psychomotor slowing, disorientation, confusion, extrapyramidal and cerebellar symptoms or a decrease in consciousness occur. Clinically, overt HE is preceded by minimal alterations of cerebral function that can only be detected by neuropsychological or neurophysiological measures, but which nevertheless interfere with the patient's daily living. Rapidly progressing spastic paraparesis (hepatic myelopathy) is a rare complication of cirrhosis. In contrast to HE, it does not respond to blood ammonia lowering therapies but must be considered as an indication for urgent liver transplantation. Cognitive dysfunction has recently been detected in hepatitis C virus (HCV)-infected patients with normal liver function. The patients presented with severe fatigue, cognitive dysfunction and mood disorders. Alterations in brain metabolites, as detected by magnetic resonance spectroscopy, indicated central nervous system alteration in these patients. In contrast to patients with HE, HCV-infected patients did not show motor symptoms or deficits in visual perception, but considerable deficits in attention and concentration ability.

Functional imaging of the brain in patients with liver cirrhosis.

Brain imaging techniques have provided substantial insight into the pathophysiology of hepatic encephalopathy (HE). Magnetic resonance imaging gave hint to the fact that there is an increased deposition of manganese especially in the basal ganglia. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) showed that the preference of the basal ganglia might be due to differences in regional cerebral blood flow and an additional redistribution of blood flow from the cortex to subcortical regions in cirrhotics. PET studies using ammonia as tracer showed that the cerebral metabolism of ammonia and the permeability of the blood brain barrier for ammonia is increased in cirrhotic patients compared to healthy controls. The regional ammonia supply is in accordance with the regional blood flow. In accordance with these findings fluorodesoxyglucose-PET-studies of the brain in cirrhotics showed characteristic alterations of glucose utilisation in the patients with a relative decrease of the glucose utilisation of the cingulate gyrus, the frontomedial, frontolateral, and parieto-occipital cortex, while the glucose utilisation of the basal ganglia, the hippocampus, and the cerebellum was relatively increased. These findings fit well with the clinical characteristics of early stages of HE such as deficits in attention, visuo-spatial orientation, visuo-constructive abilities, motor speed, and accuracy.

Comparison of perfusion computed tomography with diffusion-weighted magnetic resonance imaging in hyperacute ischemic stroke.

OBJECTIVE: In this study, perfusion CT and diffusion-weighted magnetic resonance imaging (DWI) were compared as means of assessing the ischemic brain in hyperacute stroke. METHODS: Twenty patients with ischemic stroke underwent perfusion computed tomography (CT) and magnetic resonance imaging (MRI) studies <3 hours after stroke onset. Cerebral blood flow thresholds were used to delineate the ischemic lesion, penumbra, and infarct. Correlations between the volume of the hypoperfused areas, the abnormality volume in admission DWI and follow-up CT/MRI studies, and the clinical National Institutes of Health Stroke Scale (NIHSS) scores were performed. RESULTS: The volume of the ischemic (core and penumbra) lesion on admission perfusion CT was correlated with the volume of admission DWI abnormalities (r=0.89, P=0.001). The infarcted core tissue volume (on admission CT) correlated more strongly (r=0.77, P=0.0001) than the admission DWI abnormality volume (r=0.69, P=0.002) with the follow-up infarct volume on fluid-attenuated inversion recovery images. A correlation was demonstrated between infarct volume in perfusion CT and follow-up DWI abnormality volume (r=0.89, r=0.77, P=0.002). Significant correlations were found between ischemic and infarct region volumes in perfusion CT and NIHSS admission and follow-up scores (P < or = 0.01). CONCLUSIONS: Both imaging modalities provide a sufficient assessment of the hyperacute brain infarct, with significant correlation between them and the clinical condition at admission. Perfusion CT allows differentiation of the penumbra and infarct core region with significant predictive value of follow-up infarct volume and clinical outcome.

Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy.

BACKGROUND/AIMS: Up to 50% of patients infected with the hepatitis C virus (HCV) complain of chronic fatigue and difficulties in concentration and memory. The aim of the present study was to seek evidence for the presence of central nervous system involvement in HCV infected patients with only mild liver disease. METHODS: Thirty HCV infected patients with normal liver function, 15 of whom were identified as having mild and 15 moderate to severe fatigue using the fatigue impact scale, underwent neurological and neuropsychological examination, electroencephalography (EEG) and cerebral proton magnetic resonance imaging (MRI) and spectroscopy (MRS). Fifteen healthy volunteers, matched for age and educational attainment, served as controls. RESULTS: In comparison to the healthy controls the patients with HCV infection showed evidence of cognitive impairment, primarily attention and higher executive functions, higher levels of anxiety and depression and impairment of quality of life. In addition they showed a significant decrease of the N-acetyl-aspartate/creatine ratio in the cerebral cortex on 1H MRS while the EEG was slowed in 25%. In general the deficits were more marked in the patients with moderate rather than mild fatigue. CONCLUSIONS: The data provide evidence of central nervous system involvement in patients with HCV infection.

Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis.

Clinical and histopathological findings hint at regional differences in the brain's sensitivity to metabolic changes in cirrhosis. The aim of the present study was to examine regional differences in cerebral ammonia metabolism in patients with cirrhosis and grade 0-to-I hepatic encephalopathy (HE). (13)N-ammonia, (15)O-water positron emission tomography (PET) and magnetic resonance imaging (MRI) were performed. Quantitative values of cerebral blood flow (CBF) and the initial cerebral ammonia uptake rate (K1) were derived for several regions of interest from images of the desired parameters after interactive coregistration with the patients' MRI-studies. CBF (mL/mL/min), K1 (mL/mL/min), and the ammonia extraction fraction (K1/CBF) showed marked regional variance with the highest levels in the thalamus, the lenticular nucleus, and the cerebellum. In conclusion, the regional differences in cerebral ammonia uptake correspond to the distribution of histopathological changes in the brain of patients with cirrhosis as well as clinical features of HE, characterized by signs of basal ganglia and cerebellar dysfunction with corresponding signs of functional impairment, especially of the frontal cortex and cingulate gyrus.